PT  - JOURNAL ARTICLE
AU  - Ngwaga, Tshegofatso
AU  - Chauhan, Deepika
AU  - Salberg, Abigail G.
AU  - Shames, Stephanie R.
TI  - Effector-mediated subversion of proteasome activator (PA)28αβ enhances lysosomal targeting of <em>Legionella pneumophila</em> within cytokine-activated macrophages
AID  - 10.1101/2021.12.27.473672
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.12.27.473672
4099  - http://biorxiv.org/content/early/2022/04/19/2021.12.27.473672.short
4100  - http://biorxiv.org/content/early/2022/04/19/2021.12.27.473672.full
AB  - Legionella pneumophila is a natural pathogen of protozoa that causes Legionnaires’ Disease pneumonia via replication within macrophages using hundreds of translocated effector proteins. In metazoans, effectors can also enhance pathogen clearance via effector-triggered immunity. The effector LegC4 confers a fitness disadvantage on L. pneumophila uniquely within cytokine-activated macrophages, but the mechanism is unknown. Here, we demonstrate that LegC4 restriction occurs via subversion of proteasome activator (PA)28αß, which is induced by cytokines and functions to resolve oxidative stress. LegC4 impaired resolution of oxidative stress and LegC4-mediated restriction was abolished within PA28αß-deficient macrophages. Impaired proteasome activity upregulates lysosomal degradation pathways and, indeed, subversion PA28αβ by LegC4 enhanced lysosomal fusion with the Legionella-containing vacuole. PA28αβ has been traditionally associated with antigen presentation; however, our data support a new model whereby subversion of PA28αβ enhances macrophage cell-autonomous immunity against L. pneumophila. This work provides a solid foundation to evaluate induced proteasome regulators as mediators of innate immunity.Competing Interest StatementThe authors have declared no competing interest.